Natural killer cells accumulate in lung-draining lymph nodes and regulate airway eosinophilia in a murine model of asthma.

Increasing evidence suggests a key role for the innate immune system in asthma development. Although the role of Natural Killer (NK) cells in allergic asthma is poorly known, modifications of the blood NK cell populations have been found in asthmatic and/or allergic patients. Their repartition and activation status in the inflammatory (lungs) and the regulatory (draining lymph nodes) sites of the allergic reaction is unknown. The aim of our study was to monitor NK cell migration pattern and activation status and to investigate the consequences of NK cell depletion during allergic airway reaction in a mouse model. Ovalbumin sensitization and challenges of BALB/cByJ mice had no effect on the total number of lung NK cells but significantly decreased the number of most mature NK cells and increased the level of the activation marker CD86. In the lung-draining mediastinal lymph nodes, ovalbumin sensitization and challenges led to increased number of NK cells, and more precisely, immature NK cells and increased expression of CD86. Ovalbumin-sensitized mice also exhibited increased percentage of proliferating NK cells in lung-draining mediastinal lymph nodes. Anti-ASGM1 antibody treatment depleted most NK cells and decreased bronchoalveolar lavage eosinophilia but did not modify airway responsiveness. Altogether, our study shows that pulmonary allergic sensitization induces modification in the NK cell compartment at the inflammatory and regulatory sites and suggests that NK cells may participate in the regulation of the asthmatic response and, more particularly, to the allergic airway eosinophilia.

A1/Bfl-1 expression is restricted to TCR engagement in T lymphocytes.

We analyzed regulation of the prosurvival Bcl-2 homologue A1, following T-cell receptor (TCR) or cytokine receptor engagement. Activation of CD4(+) or CD8(+) T cells by antigenic peptides induced an early but transient IL-2-independent expression of A1 and Bcl-xl mRNA and proteins, whereas expression of Bcl-2 was delayed and required IL-2. Cytokines such as IL-2, IL-4, IL-7 or IL-15 prevented apoptosis of activated T cells that effect being associated with the maintenance of Bcl-2, but not of A1 expression. However, restimulation of activated or posteffector T cells with antigenic peptide strongly upregulated A1 mRNA and maintained A1 protein expression. IL-4, IL-7 or IL-15 also prevented cell death of naive T cells. In those cells, cytokines upregulated Bcl-2, but not A1 expression. Therefore, in naive, activated and posteffector T cells, expression of A1 is dependent on TCR but not on cytokine receptor engagement, indicating that A1 is differently regulated from Bcl-xl and Bcl-2.

Protection against experimental autoimmune encephalomyelitis by a proteasome modulator.

The capacity of interferon beta to alter the course of multiple sclerosis has promoted a new therapeutic concept, based upon the modulation of the immune response rather than its suppression. As the proteasome plays a crucial role in the control of the inflammatory process and immune cell survival, targeting the proteasome appears as a novel approach for the prevention and treatment of inflammatory autoimmune diseases. We have previously shown that ritonavir, an HIV-1 protease inhibitor used in AIDS therapy, can modulate the proteasome function by inhibiting the chymotrypsin-like activity and enhancing the trypsin-like activity. We have, therefore, explored its therapeutic potential on experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis, in Lewis rats and SJL mice. Daily administration of ritonavir during autoimmune antigen stimulation prevented clinical symptoms of EAE in a dose- and time-dependent manner. This protection was accompanied by an inhibition of the mononuclear cell infiltration into the central nervous system usually observed in EAE. Despite a complete absence of clinical symptoms during first EAE induction, ritonavir-treated animals became resistant to further induction of EAE, suggesting an immune mechanism of protection. These results suggest that proteasome modulation using ritonavir or analogues may be of interest for patients with multiple sclerosis.

Involvement of inhibitory NKRs in the survival of a subset of memory-phenotype CD8+ T cells.

Inhibitory natural killer receptors (NKRs) such as killer cell immunoglobulin-like receptors (KIRs) in humans and Ly49 molecules in mice are expressed on NK cells and recognize multiple major histocompatibility (MHC) class I proteins. In humans and mice, a subset of CD8+ T cells also expresses NKRs and harbors a memory phenotype. Using mice that are transgenic for KIR2DL3 and its cognate HLA-Cw3 ligand, we show that engagement of inhibitory NKRs selectively drives the in vivo accumulation of a subset of memory-phenotype CD8+ T cells that express the beta chain of the interleukin 2 receptor. In vitro, recognition of MHC class I molecules by inhibitory NKRs on T cells down-regulated activation-induced cell death. These results unveil an MHC class I-dependent pathway that promotes the survival of a subset of memory-phenotype CD8+ T cells and also reveal an unexpected biological function for inhibitory NKRs on T cells.

Early neurobehavioral disorders after cardiac surgery: a comparative analysis of coronary artery bypass graft surgery and valve replacement.

OBJECTIVE: To analyze neurobehavioral disorders in the early postoperative period after valve replacement and coronary artery bypass graft (CABG) surgery. DESIGN: Prospective study. SETTING: University hospital. PARTICIPANTS: Patients undergoing elective cardiac surgery with cardiopulmonary bypass; 42 patients in the valve replacement surgery group and 42 patients in the CABG surgery group, with both groups matched post hoc for age, sex, and preoperative cognitive status. MEASUREMENTS AND MAIN RESULTS: All subjects were investigated preoperatively as well as 2 and 7 days postoperatively with a comprehensive neuropsychologic and neuropsychiatric assessment. The groups did not significantly differ with respect to the incidence of postoperative neuropsychiatric disorders. Valve replacement surgery patients exhibited more severe neuropsychologic deficits and showed a slower recovery than patients who underwent CABG surgery. In both groups, postoperative neuropsychologic alterations were most marked in fluency, arithmetic, and memory performance. CONCLUSION: These results indicate that patients after valve replacement surgery have a higher risk of postoperative neuropsychologic alterations mainly attributable to temporal lobe dysfunction. This finding corresponds to a specific vulnerability of hippocampal structures to transient hypoxia.

Mechanism of measles virus-induced suppression of inflammatory immune responses.

Measles virus (MV) causes profound immunosuppression, resulting in high infant mortality. The mechanisms are poorly understood, largely due to the lack of a suitable animal model. Here, we report that particular MV proteins, in the absence of MV replication, could generate a systemic immunosuppression in mice through two pathways: (1) via MV-nucleoprotein and its receptor FcgammaR on dendritic cells; and (2) via virus envelope glycoproteins and the MV-hemagglutinin cellular receptor, CD46. The effects comprise reduced hypersensitivity responses associated with impaired function of dendritic cells, decreased production of IL-12, and the loss of antigen-specific T cell proliferation. These results introduce a novel model for testing the immunosuppressive potential of anti-measles vaccines and reveal a specific mechanism of MV-induced modulation of inflammatory reactions.

Characterization at the single-cell level of naive and primed CD8 T cell cytokine responses.

The aim of this study was to characterize differences between naive and primed CD8 T cells. Our results show that (i) naive and primed CD8 T cells display similar activation thresholds, with no direct evidence for a difference in their TCR signals, and (ii) primed cells differ mainly in their capacity to secrete IFN-gamma. A comparison of the two populations at the single-cell level demonstrated that the increased production of IFN-gamma by the primed cell subset is due to a larger proportion of single cells that are able to synthesize this cytokine early following activation. These results indicate that the intrinsic effector capabilities of individual CD8 T cells expressing the same TCR are heterogeneous and that cells with identical antigen specificity but increased effector capacities are generated or selected during the primary response.

Memory CD44(int) CD8 T cells show increased proliferative responses and IFN-gamma production following antigenic challenge in vitro.

F5 TCR transgenic mice challenged in vivo with peptide generate long-lived primed CD8 T cells that hyper-proliferate in response to peptide in vitro. These primed CD8 T cells can be subdivided into three distinct populations on the basis of CD44 cell surface expression. In this report, we show that among primed CD8 T cells, those expressing intermediate levels of CD44 appear to be true memory T cells by the measurement of a variety of characteristics. Indeed, these cells hyper-proliferate in response to peptide re-stimulation in vitro, and produce IFN-gamma with faster kinetics and at higher levels than naive populations in vitro. We also show that CD8 T cells expressing high levels of CD44 express several activation markers and cycle in vivo in the absence of antigen. However, this population is unable to respond to peptide stimulation in vitro as measured by both proliferation and IFN-gamma secretion. The origin and specificity of these cells is unknown. These results provide evidence that memory CD8 T cells are functionally different from naive CD8 T cells both in terms of proliferation and cytokine secretion. They identify the CD8/CD44(int) T cells as the population responsible for hyper-reactivity in vitro.

[Neuropsychological and psychopathologic changes following cardiac surgical procedures]. / Neuropsychologische und psychopathologische Veränderungen nach kardiochirurgischen Eingriffen.

Neuropsychological and neuropsychiatric disorders following open heart surgery are estimated to occur in as many as 80 per cent of all patients. They have been recognised from the very beginning of modern heart surgery. Despite a huge amount of scientific literature, data concerning incidence, the phenomenology and duration of symptoms diverge. This finding may be explained by heterogeneous aetiopathogenetic concepts and methodological and terminological problems associated with the investigation of postoperative delirium or neuropsychological and psychopathological sequelae of cardiac surgery. Nowadays, most authors agree in respect of a multifactorial pathogenesis of cognitive deficits following cardiac surgery. Factors influencing the psychopathological and neuropsychological outcome of cardiac surgery can be divided into pre-, intra- and postoperative variables. Advanced age, degree of cardiovascular impairment and other case histories, as well as history of drug abuse, are those preoperative variables that may be responsible for a postoperative cognitive decline. The predictive value of personality traits (depression and/or anxiety), however, is most controversial. Among the intraoperative variables related to the postoperative cognitive state, are e.g. the type of operation and technical procedure (micro-/macroembolism due to the way of oxygenation, pulsatile/-non-pulsatile flow) and duration of extracorporeal circulation. In the postoperative period, the duration of intubation or ICU stay and related variables (like sleep or sensory deprivation/hyperstimulation) were identified as significant predictors of neuropsychological and psychopathological alterations. Modern research focusses on neurobiochemical markers of brain injury which may serve as early predictors of a postoperative cognitive decrease. These parameters may indicate an early postoperative diagnosis and neuroprotective treatment in patients at risk.

Neuropsychological disorders after coronary bypass surgery.

OBJECTIVES: A prospective assessment of neuropsychological impairment in the early postoperative stage after coronary bypass surgery. METHODS: Seventy patients undergoing elective coronary bypass surgery (CABG) were investigated preoperatively, two to three and five to nine days postoperatively with a comprehensive neuropsychological assessment including orientation, word fluency, naming, arithmetic, memory, and visuoconstructive tasks. RESULTS: Patients exhibited significant early postoperative impairment affecting all tasks but naming. Except for the orientation measurement, most patients recovered by the fifth to ninth postoperative day. Only six patients had delirium according to DSM III-R criteria on the second or third postoperative day. Cluster analysis of neuropsychological data obtained on the second to third postoperative day identified 10 patients who were cognitively compromised. As a group, these patients had required a greater number of defibrillations and exhibited lower cardiac indices postoperatively. Preoperatively, patients at risk for postoperative dysfunction were characterised by lower verbal memory, word fluency, and clock orientation scores. CONCLUSIONS: Simple preoperative neuropsychological assessment may be helpful and clinically applicable in identifying patients at risk for postoperative cognitive dysfunction and may contribute to improve postoperative management aiming at the prevention of delirium or other transient neuropsychological disorders.